Abstract

An increase in hepatic glucose production (HGP) represents a key feature of type 2 diabetes. This deficiency in metabolic control of glucose production critically depends on enhanced signaling through hepatic glucagon receptors (GCGRs). Here, we have demonstrated that selective inactivation of the GPCR-associated protein β-arrestin 2 in hepatocytes of adult mice results in greatly increased hepatic GCGR signaling, leading to striking deficits in glucose homeostasis. However, hepatocyte-specific β-arrestin 2 deficiency did not affect hepatic insulin sensitivity or β-adrenergic signaling. Adult mice lacking β-arrestin 1 selectively in hepatocytes did not show any changes in glucose homeostasis. Importantly, hepatocyte-specific overexpression of β-arrestin 2 greatly reduced hepatic GCGR signaling and protected mice against the metabolic deficits caused by the consumption of a high-fat diet. Our data support the concept that strategies aimed at enhancing hepatic β-arrestin 2 activity could prove useful for suppressing HGP for therapeutic purposes.

Figure 1

(A) i.p. ITT. Data are shown as mean ± SEM (n = 9 mice per group, 20-week-old males). (B) Insulin-induced phosphorylation of AKT and GSK3α/β remains unaffected by the lack of β-arrestin 2 in hepatocytes. Primary hepatocytes prepared from hep-barr2–KO and control mice were incubated with insulin (10 nM) or saline for 15 minutes. Cell lysates were used for immunoblotting with the indicated antibodies. Representative blots are shown. See complete unedited blots in the supplemental material. (C) Quantification via densitometry (NIH ImageJ software) of the immunoblotting data shown in B. Phospho-protein expression levels were normalized by total AKT or total GSK3α/β expression, respectively. Data represent mean ± SEM (n = 5 mice per group, 16- to 20-week-old males). (D and E). Hyperinsulinemic euglycemic clamp studies. In D, the time course of blood glucose and GIR are shown. Data in panel E were obtained during the steady-state period of the clamp (gray area in D). Values are shown as mean ± SEM (n = 3 or 4 mice per group, 20-week-old males).